tbuckley/cabot-search huggingface dataset:
Neural Mechanisms and Psychology of Psychedelic Ego Dissolution
Authors: Devon Stoliker, Gary F. Egan, Karl J. Friston, Adeel Razi
Journal: Pharmacological Reviews (2022)

Neuroimaging studies of psychedelics have advanced our understanding of hierarchical brain organization and the mechanisms underlying their subjective and therapeutic effects. The primary mechanism of action of classic psychedelics is binding to serotonergic 5-HT2A receptors. Agonist activity at these receptors leads to neuromodulatory changes in synaptic efficacy that can have a profound effect on hierarchical message-passing in the brain. Here, we review the cognitive and neuroimaging evidence for the effects of psychedelics: in particular, their influence on selfhood and subject-object boundaries-known as ego dissolution-surmised to underwrite their subjective and therapeutic effects. Agonism of 5-HT2A receptors, located at the apex of the cortical hierarchy, may have a particularly powerful effect on sentience and consciousness. These effects can endure well after the pharmacological half-life, suggesting that psychedelics may have effects on neural plasticity that may play a role in their therapeutic efficacy. Psychologically, this may be accompanied by a disarming of ego resistance that increases the repertoire of perceptual hypotheses and affords alternate pathways for thought and behavior, including those that undergird selfhood. We consider the interaction between serotonergic neuromodulation and sentience through the lens of hierarchical predictive coding, which speaks to the value of psychedelics in understanding how we make sense of the world and specific predictions about effective connectivity in cortical hierarchies that can be tested using functional neuroimaging. SIGNIFICANCE STATEMENT: Classic psychedelics bind to serotonergic 5-HT2A receptors. Their agonist activity at these receptors leads to neuromodulatory changes in synaptic efficacy, resulting in a profound effect on information processing in the brain. Here, we synthesize an abundance of brain imaging research with pharmacological and psychological interpretations informed by the framework of predictive coding. Moreover, predictive coding is suggested to offer more sophisticated interpretations of neuroimaging findings by bridging the role between the 5-HT2A receptors and large-scale brain networks.
Changing Cerebral Blood Flow, Glucose Metabolism, and Dopamine Binding Through Transcranial Magnetic Stimulation: A Systematic Review of Transcranial Magnetic Stimulation-Positron Emission Tomography Literature
Authors: Kaitlin R. Kinney, Colleen A. Hanlon
Journal: Pharmacological Reviews (2022)

Transcranial magnetic stimulation (TMS) is a noninvasive neuromodulation tool currently used as a treatment in multiple psychiatric and neurologic disorders. Despite its widespread use, we have an incomplete understanding of the way in which acute and chronic sessions of TMS affect various neural and vascular systems. This systematic review summarizes the state of our knowledge regarding the effects TMS may be having on cerebral blood flow, glucose metabolism, and neurotransmitter release. Forty-five studies were identified. Several key themes emerged: 1) TMS transiently increases cerebral blood flow in the area under the coil; 2) TMS to the prefrontal cortex increases glucose metabolism in the anterior cingulate cortex of patients with depression; and 3) TMS to the motor cortex and prefrontal cortex decreases dopamine receptor availability in the ipsilateral putamen and caudate respectively. There is, however, a paucity of literature regarding the effects TMS may have on other neurotransmitter and neuropeptide systems of interest, all of which may shed vital light on existing biologic mechanisms and future therapeutic development. <h3>Significance Statement</h3> Transcranial magnetic stimulation (TMS) is a noninvasive neuromodulation tool currently used as a treatment in multiple psychiatric and neurologic disorders. This systematic review summarizes the state of our knowledge regarding the effects TMS on cerebral blood flow, glucose metabolism, and neurotransmitter release.
Exploring Intestinal Surface Receptors in Oral Nanoinsulin Delivery
Authors: Carlynne Choy, Lee Yong Lim, Lai Wah Chan, Zhixiang Cui, Shirui Mao, Tin Wui Wong
Journal: Pharmacological Reviews (2022)

Subcutaneous and inhaled insulins are associated with needle phobia, lipohypertrophy, lipodystrophy, and cough in diabetes treatment. Oral nanoinsulin has been developed, reaping the physiologic benefits of peroral administration. This review profiles intestinal receptors exploitable in targeted delivery of oral nanoinsulin. Intestinal receptor targeting improves oral insulin bioavailability and sustains blood glucose–lowering response. Nonetheless, these studies are conducted in small animal models with no optimization of insulin dose, targeting ligand type and content, and physicochemical and molecular biologic characteristics of nanoparticles against the in vivo/clinical diabetes responses as a function of the intestinal receptor population characteristics with diabetes progression. The interactive effects between nanoinsulin and antidiabetic drugs on intestinal receptors, including their up-/downregulation, are uncertain. Sweet taste receptors upregulate SGLT-1, and both have an undefined role as new intestinal targets of nanoinsulin. Receptor targeting of oral nanoinsulin represents a viable approach that is relatively green, requiring an in-depth development of the relationship between receptors and their pathophysiological profiles with physicochemical attributes of the oral nanoinsulin. <h3>Significance Statement</h3> Intestinal receptor targeting of oral nanoinsulin improves its bioavailability with sustained blood glucose–lowering response. Exploring new intestinal receptor and tailoring the design of oral nanoinsulin to the pathophysiological state of diabetic patients is imperative to raise the insulin performance to a comparable level as the injection products.
Serum Prostate-Specific Antigen in a Community-Based Population of Healthy Men
Authors: Joseph E. Oesterling
Journal: JAMA (1993)

<h3>Objective.</h3> —To define the characteristics of serum prostate-specific antigen (PSA) in a population of healthy men without clinically evident prostate cancer, but who are at risk for developing the malignancy. The influence of patient age and prostatic size on the serum PSA concentration was assessed in order to use PSA more appropriately to detect clinically significant prostate cancer at an early, potentially curable stage. <h3>Design.</h3> —Prospective, community-based study. <h3>Participants.</h3> —Between December 1989 and March 1991, 2119 healthy men aged 40 to 79 years from Olmsted County, Minnesota, were entered into a prospective study to assess the natural history of benign prostatic hyperplasia. Of these, 537 (25%) were randomly chosen to participate in a detailed clinical examination that included a serum PSA determination (Tandem-R PSA assay), digital rectal examination, and transrectal ultrasonography. Four hundred seventy-one (88%) completed the prostatic evaluation and had no evidence of prostate cancer by any of these three diagnostic tests; these men formed the study population on which all analyses were performed. <h3>Main Outcome Measure.</h3> —Serum PSA concentration, prostatic volume, and PSA density (serum PSA level/prostatic volume) as a function of patient age. <h3>Results.</h3> —The serum PSA concentration is correlated with patient age (<i>r</i>=.43;<i>P</i>&lt;.0001) and prostatic volume (<i>r</i>=.55;<i>P</i>&lt;.0001). Prostatic volume, in turn, is directly correlated with patient age (<i>r</i>=.43;<i>P</i>&lt;.0001), whereas the PSA density value is only weakly correlated with patient age (<i>r</i>=.25;<i>P</i>&lt;.001). For a healthy 60-year-old man with no evidence of prostate cancer, the serum PSA concentration increases by approximately 3.2% per year (0.04 ng/mL per year). The recommended reference range for serum PSA (95th percentile) for men aged 40 to 49 years is 0.0 to 2.5 ng/mL; for 50 to 59 years, 0.0 to 3.5 ng/mL; 60 to 69 years, 0.0 to 4.5 ng/mL; and 70 to 79 years, 0.0 to 6.5 ng/mL. <h3>Conclusions.</h3> —The serum PSA concentration is directly correlated with patient age and prostatic volume, the latter of which also is directly related to age. Thus, rather than rely on a single reference range for men of all age groups, it is more appropriate to have age-specific reference ranges. These age-specific reference ranges have the potential to make serum PSA a more discriminating tumor marker for detecting clinically significant cancers in older men (increasing specificity) and to find more potentially curable cancers in younger men (increasing sensitivity). (<i>JAMA</i>. 1993;270:860-864)
Diabetic cardiomyopathy: the need for adjusting experimental models to meet clinical reality
Authors: Frank Lezoualc’h, Lina Badimon, Hana Baker, Monique Bernard, Gabor Czibik, Rudolf A de Boer, Thomas D’Humières, Micheline Kergoat, Mark Kowala, Jennifer Rieusset, Gemma Vilahur, Maximin Détrait, Chris Watson, Geneviève A Derumeaux
Journal: Cardiovascular Research (2022)

Abstract Diabetic cardiomyopathy (CM), occurring in the absence of hypertension, coronary artery disease, and valvular or congenital heart disease, is now recognized as a distinct, multifactorial disease leading to ventricular hypertrophy and abnormal myocardial contractility that correlates with an array of complex molecular and cellular changes. Animal models provide the unique opportunity to investigate mechanistic aspects of diabetic CM, but important caveats exist when extrapolating findings obtained from preclinical models of diabetes to humans. Indeed, animal models do not recapitulate the complexity of environmental factors, most notably the duration of the exposure to insulin resistance that may play a crucial role in the development of diabetic CM. Moreover, most preclinical studies are performed in animals with uncontrolled or poorly controlled diabetes, whereas patients tend to undergo therapeutic intervention. Finally, whilst type 2 diabetes mellitus prevalence trajectory mainly increases at 40- &amp;lt; 75 years (with a currently alarming increase at younger ages, however), it is a legitimate concern how closely rodent models employing young animals recapitulate the disease developing in old people. The aim of this review is to identify the current limitations of rodent models and to discuss how future mechanistic and preclinical studies should integrate key confounding factors to better mimic the diabetic CM phenotype.
Scientific and regulatory activities initiated by the U.S. Food and drug administration to foster approvals of generic dry powder inhalers: Bioequivalence perspective
Authors: Bryan Newman, Andrew Babiskin, Elizabeth Bielski, Susan Boc, Sneha Dhapare, Lanyan Fang, Katharine Feibus, Anubhav Kaviratna, Bing V. Li, Markham C. Luke, Tian Ma, Michael Spagnola, Ross L. Walenga, Zhong Wang, Liang Zhao, Nashwa El-Gendy, Craig M. Bertha, Mohammed Abd El-Shafy, Dhaval K. Gaglani
Journal: Advanced Drug Delivery Reviews (2022)
Foodborne Outbreak of Group A Rotavirus Gastroenteritis Among College Students--District of Columbia, March-April 2000
Journal: JAMA (2001)

On March 31, student health services at a university in the District of Columbia (DC) notified the DC health department that an increased number of students had become ill with acute gastroenteritis beginning March 29. Some ill students reported eating tuna or chicken salad sandwiches from dining hall A on campus. On March 31, the DC health department initiated an outbreak investigation. This report summarizes results of the investigation, which indicated that group A rotavirus transmitted by food was the cause of the outbreak.
Hepatic encephalopathy is not a contraindication to pre-emptive TIPS in high-risk patients with cirrhosis with variceal bleeding
Authors: Marika Rudler, Virginia Hernández-Gea, Bogdan Dumitru Procopet, Alvaro Giráldez, Lucio Amitrano, Càndid Villanueva, Luis Ibañez, Gilberto Silva-Junior, Joan Genesca, Christophe Bureau, Jonel Trebicka, Rafael Bañares, Aleksander Krag, Elba Llop, Wim Laleman, Jose Maria Palazon, Jose Castellote, Susana Rodrigues, Lise Lotte Gluud, Carlos Noronha Ferreira, Nouria Canete, Manuel Rodríguez, Arnulf Ferlitsch, Jose Luis Mundi, Henning Gronbaek, Manuel Hernandez-Guerra, Romano Sassatelli, Alessandra Dell’era, Marco Senzolo, Juan G Abraldes, Manuel Romero-Gómez, Alexander Zipprich, Meritxell Casas, Helena Masnou, Hélène Larrue, Massimo Primignani, Frederik Nevens, Jose Luis Calleja, Remy Schwarzer, Christian Jansen, Marie-Angèle Robic, Irene Conejo, Javier Martínez Gonzalez, Maria Vega Catalina, Agustín Albillos, Edilmar Alvarado, Maria Anna Guardascione, Maxime Mallet, Simona Tripon, Georgina Casanovas, Jaume Bosch, Juan-Carlos Garcia-Pagan, Dominique Thabut
Journal: Gut (2022)

A pre-emptive transjugular intrahepatic portosystemic shunt (pTIPS) reduces mortality in high-risk patients with cirrhosis (Child-Pugh C/B+active bleeding) with acute variceal bleeding (AVB). Real-life studies point out that <15% of patients eligible for pTIPS ultimately undergo transjugular intrahepatic portosystemic shunt (TIPS) due to concerns about hepatic encephalopathy (HE). The outcome of patients undergoing pTIPS with HE is unknown. We aimed to (1) assess the prevalence of HE in patients with AVB; (2) evaluate the outcome of patients presenting HE at admission after pTIPS; and (3) determine if HE at admission is a risk factor for death and post-TIPS HE.This is an observational study including 2138 patients from 34 centres between October 2011 and May 2015. Placement of pTIPS was based on individual centre policy. Patients were followed up to 1 year, death or liver transplantation.671 of 2138 patients were considered at high risk, 66 received pTIPS and 605 endoscopic+drug treatment. At admission, HE was significantly more frequent in high-risk than in low-risk patients (39.2% vs 10.6%, p<0.001). In high-risk patients with HE at admission, pTIPS was associated with a lower 1-year mortality than endoscopic+drug (HR 0.374, 95% CI 0.166 to 0.845, p=0.0181). The incidence of HE was not different between patients treated with pTIPS and endoscopic+drug (38.2% vs 38.7%, p=0.9721), even in patients with HE at admission (56.4% vs 58.7%, p=0.4594). Age >56, shock, Model for End-Stage Liver Disease score >15, endoscopic+drug treatment and HE at admission were independent factors of death in high-risk patients.pTIPS is associated with better survival than endoscopic treatment in high-risk patients with cirrhosis with variceal bleeding displaying HE at admission.
Comparison of Multidimensional Frailty Instruments for Estimation of Long-term Patient-Centered Outcomes After Cardiac Surgery
Authors: Louise Y. Sun, Habib Jabagi, Jiming Fang, Douglas S. Lee
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Little is known about the performance of available frailty instruments in estimating patient-relevant outcomes after cardiac surgery. <h3>Objective</h3> To examine how well the Johns Hopkins Adjusted Clinical Groups (ACG) frailty indicator, the Hospital Frailty Risk Score (HFRS), and the Preoperative Frailty Index (PFI) estimate long-term patient-centered outcomes after cardiac surgery. <h3>Design, Setting, and Participants</h3> This retrospective cohort study was conducted in Ontario, Canada, among residents 18 years and older who underwent coronary artery bypass grafting or aortic, mitral or tricuspid valve, or thoracic aorta surgery between October 2008 and March 2017. Long-term care residents, those with discordant surgical encounters, and those receiving dialysis or dependent on a ventilator within 90 days were excluded. Statistical analysis was conducted from July 2021 to January 2022. <h3>Main Outcomes and Measures</h3> The primary outcome was patient-defined adverse cardiovascular and noncardiovascular events (PACE), defined as the composite of severe stroke, heart failure, long-term care admission, new-onset dialysis, and ventilator dependence. Secondary outcomes included mortality and individual PACE events. The association between frailty and PACE was examined using cause-specific hazard models with death as a competing risk, and the association between frailty and death was examined using Cox models. Areas under the receiver operating characteristic curve (AUROC) were determined over 10 years of follow-up for each frailty instrument. <h3>Results</h3> Of 88 456 patients (22 924 [25.9%] female; mean [SD] age, 66.3 [11.1] years), 14 935 (16.9%) were frail according to ACG criteria, 63 095 (71.3%) according to HFRS, and 76 754 (86.8%) according to PFI. Patients with frailty were more likely to be older, female, and rural residents; to have lower income and multimorbidity; and to undergo urgent surgery. Patients meeting ACG criteria (hazard ratio [HR], 1.66; 95% CI, 1.60-1.71) and those with higher HFRS scores (HR per 1.0-point increment, 1.10; 95% CI, 1.09-1.10) and PFI scores (HR per 0.1-point increment, 1.75; 95% CI, 1.73-1.78) had higher rates of PACE. Similar magnitudes of association were observed for each frailty instrument with death and individual PACE components. The HFRS had the highest AUROC for estimating PACE during the first 2 years and death during the first 4 years, after which the PFI had the highest AUROC. <h3>Conclusions and Relevance</h3> These findings could help to tailor the use of frailty instruments by outcome and follow-up duration, thus optimizing preoperative risk stratification, patient-centered decision-making, candidate selection for prehabilitation, and personalized monitoring and health resource planning in patients undergoing cardiac surgery.
Patient and Family Representation in Randomized Clinical Trials Published in 3 Medical and Surgical Journals
Authors: Nissim Benizri, Sophie Hallot, Karen Burns, Michael Goldfarb
Journal: JAMA Network Open (2022)

Patient and family engagement in research may improve the design, conduct, and dissemination of clinical research, but little is known about whether these stakeholder groups are involved in the design and conduct of randomized clinical trials.To characterize the involvement and role of patient and family representatives in the design and conduct of randomized clinical trials by reviewing randomized clinical trials from 3 peer-reviewed medical and surgical journals with high impact factors.In this systematic review, the first 50 consecutive randomized clinical trials published on or after January 1, 2021, until September 30, 2021, from each of 3 medical and surgical journals with high impact factors were reviewed for patient or family involvement in trial design and/or conduct. The manuscript, supplemental data, and trial registry records were searched for trial design and governance structures. Two independent, blinded reviewers screened citations and extracted data. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.Only 7 of 150 randomized clinical trials (5%) reported patient or family representation in their study design or conduct. Most studies with patient or family representation (n = 5) were from a single journal. Stakeholder involvement was mainly in the execution phase (n = 7), although in 2 studies stakeholders were also involved in the translation phase.The findings of this systematic review suggest that patient or family involvement in the design and conduct of randomized clinical trials in the publications with high impact factors is lacking. We found that when patient or family groups are involved in research, the focus was mainly on the execution phase of research design. There is a need to increase stakeholder involvement in the research design, conduct, and translation of randomized clinical trials.
Hypophosphataemia following ferric derisomaltose and ferric carboxymaltose in patients with iron deficiency anaemia due to inflammatory bowel disease (PHOSPHARE-IBD): a randomised clinical trial
Authors: Heinz Zoller, Myles Wolf, Irina Blumenstein, Christian Primas, Stefan Lindgren, Lars L Thomsen, Walter Reinisch, Tariq Iqbal
Journal: Gut (2022)

Objective Intravenous iron—a common treatment for anaemia and iron deficiency due to inflammatory bowel disease (IBD)—can cause hypophosphataemia. This trial compared the incidence of hypophosphataemia after treatment with ferric carboxymaltose (FCM) or ferric derisomaltose (FDI). Design This randomised, double-blind, clinical trial was conducted at 20 outpatient hospital clinics in Europe (Austria, Denmark, Germany, Sweden, UK). Adults with IBD and iron deficiency anaemia (IDA) were randomised 1:1 to receive FCM or FDI at baseline and at Day 35 using identical haemoglobin- and weight-based dosing regimens. The primary outcome was the incidence of hypophosphataemia (serum phosphate &lt;2.0 mg/dL) at any time from baseline to Day 35 in the safety analysis set (all patients who received ≥1 dose of study drug). Markers of mineral and bone homeostasis, and patient-reported fatigue scores, were measured. Results A total of 156 patients were screened; 97 (49 FDI, 48 FCM) were included and treated. Incident hypophosphataemia occurred in 8.3% (4/48) FDI-treated patients and in 51.0% (25/49) FCM-treated patients (adjusted risk difference: −42.8% (95% CI –57.1% to –24.6%) p&lt;0.0001). Both iron formulations corrected IDA. Patient-reported fatigue scores improved in both groups, but more slowly and to a lesser extent with FCM than FDI; slower improvement in fatigue was associated with greater decrease in phosphate concentration. Conclusion Despite comparably effective treatment of IDA, FCM caused a significantly higher rate of hypophosphataemia than FDI. Further studies are needed to address the longer-term clinical consequences of hypophosphataemia and to investigate mechanisms underpinning the differential effects of FCM and FDI on patient-reported fatigue.